title: A unique mutation of ALK2, G356D, found in a patient with fibrodysplasia ossificans progressiva is a moderately activated BMP type I receptor.
abstract: Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant congenital disorder characterized by progressive heterotopic bone formation in muscle tissues. A common mutation among FOP patients has been identified in ALK2, ALK2(R206H), which encodes a constitutively active bone morphogenetic protein (BMP) receptor. Recently, a unique mutation of ALK2, ALK2(G356D), was identified to be a novel mutation in a Japanese FOP patient who had unique clinical features. Over-expression of ALK2(G356D) induced phosphorylation of Smad1/5/8 and activated Id1-luc and alkaline phosphatase activity in myoblasts. However, the over-expression failed to activate phosphorylation of p38, ERK1/2, and CAGA-luc activity. These ALK2(G356D) activities were weaker than those of ALK2(R206H), and they were suppressed by a specific inhibitor of the BMP-regulated Smad pathway. These findings suggest that ALK2(G356D) induces heterotopic bone formation via activation of a BMP-regulated Smad pathway. The quantitative difference between ALK2(G356D) and ALK2(R206H) activities may have caused the phenotypic differences in these patients.
authors.affiliation: Division of Pathophysiology, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Fukuda
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kanomata
authors.forename: Junya
authors.initials: J
authors.lastname: Nojima
authors.forename: Shoichiro
authors.initials: S
authors.lastname: Kokabu
authors.forename: Masumi
authors.initials: M
authors.lastname: Akita
authors.forename: Kenji
authors.initials: K
authors.lastname: Ikebuchi
authors.forename: Eijiro
authors.initials: E
authors.lastname: Jimi
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Komori
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Maruki
authors.forename: Masaru
authors.initials: M
authors.lastname: Matsuoka
authors.forename: Kohei
authors.initials: K
authors.lastname: Miyazono
authors.forename: Konosuke
authors.initials: K
authors.lastname: Nakayama
authors.forename: Akira
authors.initials: A
authors.lastname: Nanba
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tomoda
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Okazaki
authors.forename: Akira
authors.initials: A
authors.lastname: Ohtake
authors.forename: Hiromi
authors.initials: H
authors.lastname: Oda
authors.forename: Ichiro
authors.initials: I
authors.lastname: Owan
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Yoda
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Haga
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Furuya
authors.forename: Takenobu
authors.initials: T
authors.lastname: Katagiri
mesh_terms: D030201:Activin Receptors, Type I / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D019943:Amino Acid Substitution; D000818:Animals; D001224:Aspartic Acid / Q000235:genetics / Q000378:metabolism; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002454:Cell Differentiation; D005998:Glycine / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008024:Ligands; D051379:Mice; D024510:Muscle Development / Q000187:drug effects / Q000235:genetics; D009154:Mutation; D032446:Myoblasts / Q000187:drug effects / Q000378:metabolism; D009221:Myositis Ossificans / Q000201:enzymology* / Q000235:genetics*; D010006:Osteoblasts / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism
chemical_list: D008024:Ligands; D011720:Pyrazoles; D011743:Pyrimidines; D051785:Smad Proteins; C516138:dorsomorphin; D001224:Aspartic Acid; C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I; D052005:Bone Morphogenetic Protein Receptors, Type I; D005998:Glycine